Over the past year, we have investigated whether transforming mutants of the Epidermal Growth Factor Receptor (EGFR), such as EGFRvIII, are regulated by Cbl proteins. We have shown that Cbl proteins can ubiquitinate and down regulate the oncogenic form of the EGFR, EGFRvIII. Our data indicated that the amplification and overexpression of the constitutively active EGFRvIII accounts for its transforming ability and that EGFRvIII does not escape normal negative regulatory mechanisms. We have continued to study the induction of apoptosis by TRAIL in breast cancer cells. We have shown that inhibitors of the EGFR can enhance TRAIL-mediated apoptosis in breast cancer cells which express EGFR. Interestingly, it appears that the subset of breast cancer cells which do not express estrogen receptor or ErbB-2 are most affected by EGFR inhibition. These estrogen receptor and ErbB-2 negative tumors have a poor prognosis and can only be treated with chemotherapy. Our data raise the possibility of using molecularly targeted therapy (e.g., the combination of EGFR inhibitors and TRAIL) for the treatment of these tumors.